Advanced screening methods based on liquid chromatography-mass spectrometry (LC-MS) for detection of un-predicted residues of pesticides and veterinary drugs in agriculture products and food have been reported in recent years. Without spectrum libraries like in GCMS, LC/MS/MS was initially not used in screening analysis. Whereas, high resolution LC-TOF was selected for screening analysis due to its accurate mass capability. However, with rapid progress in data acquisition technique speed like UFMS (ultrafast MS) and high MRM capacity, new generation triple quadrupole LC/MS/MS has been used for targeted screening, e.g., of over a few hundred of pesticides in one analysis. It is interesting to know the advantages and limitations of the two different screening approaches for pesticide residues in agriculture and food matrixes. We describe here a comparative study on targeted screening analysis based on MRM method on a UFMS-TQ system and un-targeted screening analysis based on high resolution MS full spectrum method on a LC-TOF system using same sample sets of mixed pesticides aiming at unveiling their capabilities and limitations in the challenging screening analysis.